Imagine a world where cancer cells could be disarmed, their growth engines silenced with pinpoint accuracy. That's the promise of a groundbreaking discovery by HKU chemists, who have engineered a novel inhibitor targeting a crucial 'switch' that fuels tumor growth. This isn't just another incremental improvement; it's a completely new approach to epigenetic drug discovery, and it could revolutionize how we treat non-small cell lung cancer (NSCLC).
Figure 1. Tumor suppression in vivo — In animal models, LS-170 treatment significantly reduced tumor volume, demonstrating its strong anti-cancer potential. (Image adapted from the relevant journal.)
Professor Xiang David Li's team at the Department of Chemistry at The University of Hong Kong (HKU), in collaboration with researchers from the Shenzhen Bay Laboratory and Tsinghua University, have achieved a major breakthrough. They've successfully created a first-in-class chemical inhibitor that selectively targets the ATAC complex. Think of the ATAC complex as a master control panel inside cells, specifically one that can activate genes promoting tumor growth. By developing a drug that can selectively disable this control panel, the team has opened a new therapeutic avenue for NSCLC. The findings, recently published in Nature Chemical Biology, have already led to multiple international patent applications.
To understand the significance, let's delve into the fascinating world of epigenetics. Inside our cells, DNA, the blueprint of life, is meticulously packaged around proteins called histones. This DNA-histone complex is known as chromatin. Chemical modifications on these histones act like genetic “switches,” determining whether certain genes are expressed (turned "on") or remain silent (turned "off"). Histone acetylation, the addition of an acetyl group, is a particularly important “on” switch, activating gene expression. This process is orchestrated by enzyme complexes called histone acetyltransferases (HATs).
The ATAC complex is a HAT complex that plays a crucial role in activating genes involved in cell growth and DNA replication. And this is the part most people miss: In cancers like NSCLC, the ATAC complex becomes hyperactive, inappropriately switching "on" numerous cancer-driving genes. This fuels uncontrolled tumor growth and spread. The challenge? Selectively inhibiting ATAC without interfering with other essential cellular processes.
Previous attempts at drug development focused on inhibiting GCN5, the catalytic subunit responsible for histone acetylation within the ATAC complex. However, GCN5 isn't exclusive to ATAC; it's also a component of several other HAT complexes. Blocking GCN5 would therefore cause significant side effects by disrupting normal cellular functions. Professor Li's team took a different, more precise approach, targeting YEATS2, a protein subunit unique to the ATAC complex. But here's where it gets controversial... some researchers argue that targeting other shared components might still be a viable strategy with careful dosage and delivery mechanisms. What do you think?
Using a technique called structure-guided design, the researchers developed a potent and highly selective inhibitor of YEATS2, named LS-170. LS-170 specifically binds to the acetyl-lysine recognition domain of YEATS2, preventing it from anchoring the ATAC complex to chromatin. In simple terms, it's like pulling the plug on the ATAC complex's power source. This displacement leads to a significant reduction in local histone acetylation and the “off” switching of oncogenes (cancer-causing genes) in NSCLC.
In NSCLC cell lines and animal models, LS-170 demonstrated impressive efficacy in suppressing tumor growth and metastasis. What's particularly exciting is that the YEATS2 gene is frequently amplified in multiple solid tumors, including lung, ovarian, and pancreatic cancers. This suggests that this targeted strategy may have broader therapeutic potential beyond just lung cancer. This research represents the first chemical approach to precisely decode the function of a specific HAT complex, revealing ATAC's distinct role in maintaining gene expression programs in cancer. It also opens doors for developing other complex-specific epigenetic drugs for human diseases.
Professor Xiang Li, one of the corresponding authors, emphasizes the significance: "In this work, we didn't just create a potent and highly specific inhibitor that can suppress tumors, we also uncovered a novel strategy to target just one epigenetic complex out of several that share the same enzyme core. This approach opens up exciting possibilities for developing highly selective, complex-specific drugs that could potentially revolutionize treatments for human diseases."
About the Research Team: The interdisciplinary collaboration was led by Professor Xiang David LI (HKU Chemistry), together with Professor Weiping WANG (HKU Pharmacology and Pharmacy), Researcher Xin LI (Shenzhen Bay Laboratory), and Professor Haitao LI (Tsinghua University). Co-first authors included Dr. Sha LIU, Dr. Yin Qiao WU, Dr. Jinzhao LIU, and Dr. Xinyi YAO.
For more details, please refer to the journal paper: https://www.nature.com/articles/s41589-025-02132-7
What are your thoughts on this novel approach to targeting cancer? Do you believe that targeting specific subunits of epigenetic complexes is the most promising avenue for drug development, or are there other strategies that hold more potential? Share your opinions in the comments below!
